Analysis Gives Edge to Pradaxa Over Xarelto

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The highest approved dose of dabigatran etexilate (Pradaxa) may yield a greater reduction in the risk of stroke or systemic embolism in patients with atrial fibrillation compared with rivaroxaban (Xarelto), an indirect comparison of new oral anticoagulants showed.

Point out that the stroke and systemic embolism risk reduction was similar when comparing a lower dose of dabigatran (110 mg BID) with rivaroxaban and when comparing apixaban with rivaroxaban and both doses of dabigatran.

The highest approved dose of dabigatran etexilate (Pradaxa) was better at reducing the risk of stroke or systemic embolism in patients with atrial fibrillation than rivaroxaban (Xarelto), an indirect comparison of the new oral anticoagulants showed.

Comparing the risk reductions seen in their respective phase III trials versus warfarin, dabigatran 150 mg twice daily (BID) was associated with a relative 26% greater reduction in the primary endpoint compared with that achieved by rivaroxaban (HR 0.74, 95% CI 0.56 to 0.97), according to Gregory Lip, MD, of the University of Birmingham in the U.K., and colleagues.

However, the risk reduction was similar when comparing a lower dose of dabigatran (110 mg BID) with rivaroxaban and when comparing apixaban with rivaroxaban and both doses of dabigatran, the researchers reported in the August 21 issue of the Journal of the American College of Cardiology.

Lip and colleagues cautioned against reading too much into the findings, saying that "any inter-trial comparison is always fraught with major difficulties, and an indirect comparison analysis has many limitations, especially with the inter-trial population differences, and thus, should not be over-interpreted."

Overall, they reported no "profound signiﬁcant differences" in efﬁcacy between apixaban and dabigatran etexilate (both doses) or rivaroxaban. "Only a head-to-head direct comparison of the different new oral anticoagulants would fully answer the question of efficacy/safety differences between the new drugs for stroke prevention in atrial fibrillation," they added.

Because of the lack of direct comparisons, the researchers performed indirect comparisons using phase III clinical trial data for dabigatran (from the RE-LY trial), rivaroxaban (from the ROCKET-AF trial), and apixaban (from the ARISTOTLE trial).

All of the trials compared the respective drugs with warfarin and showed comparable reductions in stroke or systemic embolism (dabigatran 110 mg BID, rivaroxaban) or superior efficacy (dabigatran 150 mg BID, apixaban) versus the old standard.

Dabigatran and rivaroxaban were approved by the FDA based on those results, and approval of apixaban is anticipated.

Although the patient populations in the trials of the three drugs were broadly similar, there were important differences that could not be accounted for, complicating the types of indirect comparisons made by Lip and colleagues.

RE-LY and ARISTOTLE had patients who were similar in age, gender mix, and average baseline stroke risk (average CHADS2 score of 2.1), but ROCKET-AF had patients who were slightly older and had a higher stroke risk (average CHADS2 score of 3.5).

In addition, about 20% of the RE-LY and ARISTOTLE participants had experienced a prior stroke, transient ischemic attack, or systemic embolism, whereas 55% of the ROCKET-AF population had such a history.

And the average time spent in the therapeutic range for the warfarin groups was 64% for RE-LY, 55%, for ROCKET-AF, and 62% for ARISTOTLE.

Those differences notwithstanding, the researchers found that dabigatran 150 mg BID yielded a greater reduction in the risk of stroke or systemic embolism compared with rivaroxaban, in addition to larger reductions in hemorrhagic stroke (HR 0.44, 95% CI 0.20 to 0.96) and nondisabling stroke (HR 0.60, 95% CI 0.37 to 0.97).

For ischemic stroke specifically, there were no differences between any of the agents.

In terms of safety, major bleeding was significantly lower with apixaban compared with dabigatran 150 mg BID (HR 0.74, 95% CI 0.61 to 0.91) and rivaroxaban (HR 0.66, 95% CI 0.54 to 0.81). The risk of major or clinically relevant bleeding was lower with apixaban compared with rivaroxaban (HR 0.66, 95% CI 0.58 to 0.75).

Safety endpoints were similar between apixaban and dabigatran 110 mg BID.

Rates of myocardial infarction were similar between both doses of dabigatran and apixaban, although the risk was greater with both dabigatran doses compared with rivaroxaban (HR 1.59 for the lower dose and 1.57 for the higher dose).

In an accompanying editorial, Christopher Cannon, MD, of Brigham and Women's Hospital in Boston, and Payal Kohli, MD, of the University of California San Francisco, echoed the researchers' calls for caution when interpreting the results.

"Because of the statistical limitations of such comparisons, although of some interest, we feel the differences they report on some endpoints are not robust enough to be relied upon for the clinical care of patients," Cannon and Kohli wrote.

"Instead, we would turn to direct evidence from trials and the indications put forth by the FDA to select the appropriate agent, at the dose tested, for use in the patient population studied within the trial," they said.

Lip has served as a consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Biotronik, Portola, and Boehringer Ingelheim and has been on the speakers bureau for Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and sanofi-aventis. His co-authors reported relationships with Bristol-Myers Squibb/Pfizer and Boehringer Ingelheim.

Cannon is a member of the advisory boards for Alnylam, Bristol-Myers Squibb, and Pfizer, has received financial support from them, which has been donated to charity, has received grant support from Accumetrics, AstraZeneca, Essentialis, GlaxoSmithKline, Merck, Regeneron, Sanofi, and Takeda, and has equity in Automedics Medical systems. Kohli is a member of the advisory board for Daiichi Sankyo.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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